Epidemiological, physiological and pharmacological evidence support a potential pathogenic link leading sequentially from obesity-inflammation-"insulin resistance->type 2 diabetes (T2D) and cardiovascular disease. Our basic science findings indicate that the inflammatory link is mediated by activation of the transcriptional master switch, NF-KB. Following our goals to translate basic findings to the clinic, we have identified anti-inflammatory salicylates as a potential new class of drugs for the treatment of these disorders through inhibition of the IKK[unreadable]/NF-?B pathway. Preliminary results from 2- to 4-week long, single-site clinical trials in T2D patients showed that high-doses of either aspirin (7 g/day) or salsalate (3.0 to 4.5 g/day) have pronounced and highly significant effects on many metabolic parameters, including reductions in fasting and postprandial glucose, total cholesterol, triglycerides, free fatty acids and hepatic glucose production and improvements in insulin-stimulated glucose disposal. This application aims to progress past the 'proof-of-principle'stage to determine whether IKK[unreadable]/NF-?B inhibition in general and salsalate therapy in particular might provide new avenues for treating patients with diabetes. We propose a double-masked, placebo-controlled trial for assessing the efficacy of salsalate, a safe and FDA-approved drug, initially dosed at 3.0 g/day and escalating as tolerated to 4.0 g/day. Patients with documented but poorly controlled T2D (7.0%<HbA1c <9.5%), currently being treated with diet and exercise in combination with either SFU or metformin, will be continued on their current therapy. Following a 4-week single-mask placebo run-in period, subjects will be randomized to receive placebo vs. salsalate orally for a 26-week trial period. The proposed primary endpoint is an improvement in HbA1c. Other measures of insulin resistance and the metabolic syndrome will also be monitored, including blood glucose, insulin and C-peptide levels, cholesterol and triglyceride panels, free fatty acids, blood pressure, and circulating markers and potential mediators of inflammation. While thought to be very low, the risk of potential side effects will be carefully monitored. These studies ask for the first time whether directly targeting inflammation, in this case by specifically inhibiting the IKK/NF-?B axis with salsalate (salicylate), provides new avenues for treating patients with diabetes and the metabolic syndrome.